Project 3 of the program application will test polyamine biosynthesis inhibitors (PBIs) for the treatment of HlV-associated dementia (HAD) based on the hypothesis that macrophage activation is central to the pathogenesis of this disease process. This project will be housed within the Hawaii AIDS Clinical Research Program (HACRP, PI: Cecilia Shikuma) University of Hawaii John A. Burns School of Medicine, and will be performed in close collaboration with the central core laboratory at Pathologica (Project 1, Cores B and C) and with the simian PBI trials conducted at Harvard (Project 2). Project 3 will utilize banked specimens from our NINDS-funded Hawaii Aging with HIV Cohort (HAHC) and generate data in vitro testing whether HIV-infected activated M/MOs from HAD patients are preferentially killed by PBIs. In tandem, we will identify patients with HIV cognitive impairment in real-time using an abridged combination of neuropsychological tests (NPZ-4) shown to correlate highly with the diagnosis of HAD in our patients. In these patients, we will define the unique blood M/MO gene and protein expression pattern ("ProMac Profile") associated with neurocognitive dysfunction. Finally, working closely with our collaborators, NIMH and the FDA, we propose to recruit subjects with HAD from HAHC participants who performed poorly on NPZ-4 testing, and launch, in the later half of the second year of funding, a phase 1 clinical trial of a PBI drug targeting HAD. The strengths of this proposal lie in our existing HIV clinical trials infrastructure, our neurocognitively well-characterized patient and banked specimen resources of the Hawaii Aging with HIV Cohort, and the translational research expertise of our team with a track record of close collaboration among the Program investigators. The specific aims as proposed will extend our knowledge of the pathogenesis of HAD and assess the safety and potential efficacy of a class of chemical compounds specifically directed against the likely central mechanism involved in the development of HAD. Specific Aim 1) Utilizing banked specimens, to determine in vitro the killing potential of the selected PBI(s) against activated M/MOs from subjects with HAD;and to assess various factors (HIV DNA, novel activation flow markers) potentially related to its efficacy. Hypothesis to be tested: 1) PBIs will demonstrate effective killing of activated M/MOs from HAD subjects, 2) High HIV DNA within activated M/MOs will correlate to enhanced killing by PBIs, 3)High levels of novel activation flow markers will correlate to enhanced killing by PBIs. Specific Aim 2) To define the "ProMac profile" (blood M/MO gene and protein expression patterns) associated with neurocognitive impairment using fresh specimens captured in real-time within the Hawaii Aging with HIV Cohort, and to evaluate the killing potential of PBIs against M/MOs with this profile. Hypotheses to be tested 1) A unique "ProMac profile" will be found in M/MOs isolated from HIV-infected subjects with neurocognitive dysfunction, 2) M/MOs with this "ProMac profile" will be preferentially killed by PBIs. Specific Aim 3)To conduct Phase 1 clinical trials utilizing a PBI drug in individuals with HAD. Hypothesis to be tested 1) PBIs given to patients with HAD will be safely tolerated and will result in a decrease in biomarker(s) indicative of a persistently activated M/MO phenotype.